MX2008011490A - Use of vx-702 for treating rheumatoid arthritis. - Google Patents

Abstract

The present invention relates to methods and compositions for treating RA in subjects in need thereof. The invention also relates to kits and pharmaceutical packs comprising compositions and dosage forms.

Description

COMPOSITIONS AND METHODS FOR TREATING RHEUMATOID ARTHRITIS FIELD OF THE INVENTION The present invention relates to methods for treating rheumatoid arthritis.

BACKGROUND OF THE INVENTION Rheumatoid arthritis (RA) is characterized by chronic and progressive inflammatory processes in affected joints and immunological abnormalities leading to synovial hyperplasia and destruction of the joint. Cytokines that are produced in abundant form in inflamed rheumatoid synovial fluids, such as a tumor necrosis factor-a (TNF-a), interleukin-? b (IL-? ß), IL-6 and IL-8, play crucial roles in the pathophysiology of RA. The significance of proinflammatory cytokines in the pathogenesis of RA is highlighted by the clinical effectiveness of specific inhibitors of TNF-a and IL 1ß (Kremer, Rational use of new and existing disease-modifying agents in rheumatoid arthritis, Ann, Intern Med. 134: 695-706, 2001). The treatment of RA has undergone a drastic change since the introduction of new disease-modifying antirheumatic drugs (DMARDs). However, conventional DMARDs such as methotrexate, Ref .: 196265 Gold compounds, antimalarials, cyclosporin A, leflunomide, azathioprine, sulfasalazine and d-penicillamine are all associated with toxicity although methotrexate is still the standard of care in the United States and Europe for patients with RA, often a response of less than 50% improvement. Initial data suggested that treatments that inhibit TNF-a have favorable toxicity profiles when compared to DMARDs. However, the long-term use of these treatments has led to problems regarding toxicity such as an increased risk of infection (eg, tuberculosis) and lymphoma, as well as an increased risk of systemic lupus erythematosus (Gabriel et al., A clinical and economic review of disease-modifying antirheumatic drugs, Pharmacoeconomics 19: 715-28, 2001). Treatment with etanercept (ENBREL®), a currently available anti-TNF agent that is administered by injection, in combination with methotrexate has produced a clinical remission rate of 35% (Kremer, supra). However, the discomfort of receiving injections and the side effects of anti-TNF therapy, which include the development of serious infections as well as the inability to remove active infections, indicate that alternatives to conventional DMARD therapy and anti-TNF agents are needed. for the treatment of patients with RA (Kremer, supra).

The mitogen-activated p38 protein kinase (MAPK) pathway is involved in numerous cellular processes critical for the development of RA, such as increased expression of the vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule (ICAM). ) in endothelial cells, increased expression of MAC-1 and decreased expression of L-selectin on neutrophils, activation of Thl lymphocytes and regulation by increased cytokine production by monocytes / macrophages. In addition, p38 MAPK regulates the differentiation of osteoclasts, which directly participate in bone loss. Consequently, additional therapies, dosage schedules and pharmaceutical compositions are needed to treat RA. Specifically, dosage scheme therapies and pharmaceutical compositions comprising a p37 MAPK inhibitor to treat RA are needed.

SUMMARY OF THE INVENTION The present invention provides a method for treating RA, which comprises administering VX-702, a p38 MAPK inhibitor, to a patient in need thereof. In another embodiment, the invention provides a method for treating RA, which comprises administering VX-702 and one or more other different therapeutic agents useful for treating RA.

In another embodiment, the invention provides a pharmaceutical composition comprising VX-702 and a pharmaceutically acceptable carrier. In another embodiment, the invention provides a pharmaceutical package comprising VX-702 or one of its pharmaceutical compositions. In another embodiment, the invention provides a pharmaceutical package comprising VX-702, or one of its pharmaceutical compositions, and one or more other therapeutic agents useful for treating RA. In another embodiment, the invention provides a kit comprising VX-702 or one of its pharmaceutical compositions and instructions for using VX-702 to treat RA.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the doses and methods of treating RA by the administration of VX-702, a orally available, specific and reversible inhibitor of the enzyme p38 MAPK. VX-702 has the following structure: Five Phase 1 studies of VX-702 in healthy subjects and one Phase 2a study were conducted to assess safety and tolerance of VX-702 in subjects with unstable angina pectoris (UAP), in whom percutaneous coronary intervention was scheduled with or without a stent. Multiple dose studies of VX-702 performed for up to 28 days. Doses of up to 20 mg / day were moderate to well-moderate in healthy subjects. Most of the events were mild or moderate in severity and there were few severe events. Subjects with UAP were treated with up to 40 mg / day VX-702 for 5 days and adverse events were of mild to moderate severity. In one embodiment, the invention provides pharmaceutical compositions comprising VX-702, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the RA, together with a pharmaceutically acceptable carrier. In one embodiment, VX-702, or one of its pharmaceutically acceptable salts, is provided in an amount of 1 to 20 mg in the pharmaceutical composition. In another embodiment, the invention provides a pharmaceutical composition comprising 2.5 to 15 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In another embodiment, the invention provides a pharmaceutical composition comprising 2.5 a 12.5 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In still another embodiment, the invention provides a pharmaceutical composition comprising about 4, 5, 6, 7, 8, 9, 10 or 11 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In still another embodiment, the invention provides a pharmaceutical composition comprising 4, 5, 6, 7, 8, 9, 10 or 11 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In another embodiment, the invention provides a pharmaceutical composition comprising about 5-10 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In yet another embodiment, the invention provides a pharmaceutical composition comprising 5-10 mg of VX-702, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition. In another embodiment, the invention provides a pharmaceutical composition of about 5 mg or 10 mg of VX-702. In yet another embodiment, the invention provides a pharmaceutical composition of 5 mg or 10 mg of VX-702. In another embodiment, the invention provides a pharmaceutical composition comprising about 1 mg to about 40 mg of VX-702, or a pharmaceutically acceptable salt thereof. In another embodiment, the The amount of VX-702, or a pharmaceutically acceptable salt thereof, is about 30 mg to about 40 mg of VX-702. In another embodiment, VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of about 20 mg to about 30 mg of VX-702. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, mg, 30 mg, 35 mg or 40 mg. As used herein, a specific amount or dose of VX-702 mentioned refers to this amount or dosage form of the free base of VX-702. When "a pharmaceutically acceptable salt" is mentioned of a specified amount of VX-702 (eg, "5 mg of VX-702, or one of its pharmaceutically acceptable salts"), the amount of the pharmaceutically acceptable salt is the amount that is equivalent on a molar basis of VX-702 as the specified amount of the free base form of VX-702. The amount of a pharmaceutically acceptable salt of VX-702 that is equivalent to a given amount of the free base form of VX-702 is readily determined by those skilled in the art. The molecular weight of the particular salt form of VX-702 of interest is determined and the molecular weight of this salt form is divided by the molecular weight of the free base form of VX-702 to obtain the weight ratio of the free base (salt / free base). Then multiply the amount specified from the free base form by this ratio to obtain the equivalent amount of the salt form of VX-702.

Another embodiment of this invention provides a method for treating RA in a subject in need thereof comprising administering to the subject an effective amount of VX-702, or a pharmaceutically acceptable salt thereof. In general, VX-702, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. As used herein, the terms "treat RA", "Treating RA", or "RA treatment" means reducing the severity of RA symptoms. In one embodiment, the severity of RA symptoms can be measured by evaluation of the physician and / or subject of the symptoms of the disease. These evaluations may include, among others, reduction of the number of inflamed and / or tender palpation joints, assessment of pain to the subject, self-assessment of the subject's disability, general health, overall evaluations of the physician and / or subject of the disease, and / or the acute phase response measured by laboratory tests. In one embodiment, the evaluation of disease symptoms, for example, in clinical trials, is measured by the preliminary definition of improvement of the RA (ACR2o) of the American College of Rheumatology (ACR).

In another embodiment, the evaluation of disease symptoms, for example, in clinical trials, is measured by the response criteria of the European League Against Rheumatism (EULAR). Other evaluations of RA disease symptoms are also known and could be used to evaluate the treatment of RA by VX-702. In one embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is between about 1 mg / day and 20 mg / day. In a particular embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is at least about 1 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 2.5 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 4 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 5 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 6 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 7 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 8 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 9 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 10 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 12.5 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 15 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 20 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is no more than about 20 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is no more than about 15 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is no more than about 12.5 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is no more than about 10 mg / day. In another embodiment, the amount of VX-702, or one of its pharmaceutically acceptable salts, is no more than about 5 mg / day. In another embodiment, the The amount of VX-702, or a pharmaceutically acceptable salt thereof, is no more than about 2.5 mg / day. It should be understood that these lower or higher amounts can be combined to provide preferred dose ranges for administering VX-702. For example, in one embodiment, VX-702, or a pharmaceutically acceptable salt thereof, is in an amount of about 2.5 mg to about 12.5 mg. In some of these embodiments, the amount of VX-702 is administered once per day. Alternatively, the amount of VX-702 is administered twice per day (ie, BID; ql2h) or three times per day (ie, TID; q8h). In another embodiment, VX-702, or a pharmaceutically acceptable salt thereof, is administered once a week, twice a week, every three days or every other day. In another embodiment, the amount of VX-702, or a pharmaceutically acceptable salt thereof, administered once a week, twice a week, every three days or every other day is about 2.5 mg to about 40 mg per day. In yet another embodiment, the amount of VX-702, or a pharmaceutically acceptable salt thereof, is about 2.5 mg to about 20 mg per day. In a particular embodiment, the invention provides a method of treating RA in a subject, comprising administering 2.5-12.5 mg / day VX-702, or one of its salts pharmaceutically acceptable, once a day to the subject. In another embodiment the invention provides a method of treating RA in a subject, comprising administering 5-10 mg / day VX-702, or a pharmaceutically acceptable salt thereof, once a day to the subject. In another embodiment, the invention provides a method of treating RA in a subject, comprising administering 5 or 10 mg / day of VX-702, or one of its pharmaceutically acceptable salts, once a day to the subject. As described in greater detail in Example 1, VX-702 has been tested for human beings and found to be effective in treating RA, ie to reduce the severity of RA symptoms. Subjects receiving 5 mg or 10 mg of VX-702 once per day for 12 weeks showed an improvement in their symptoms compared to subjects receiving a placebo at week 12 of treatment. Adverse events were generally mild to moderate. The methods of this invention may also involve the administration of one or more additional therapeutic agents for RA. Additional therapeutic agents that can be used with VX-702 include, without limitation, non-spheroid anti-inflammatory drugs (NSAIDS, eg, aspirin, ibuprofen, naproxen, ketoprofen, indomethacin and celecoxib), local injection and / or oral administration of anti-inflammatory spheroids. (for example, cortisone or prednisone), methotrexate, oral administration and / or intramuscular injections of gold compounds, antimalarials (eg, hydroxychloroquine), cyclosporine, leflunomide, azathioprine, sulfasalazine, d-penicillamine, cyclophosphamide and mycophenolate; or their combinations. Accordingly, in another embodiment, this invention provides a method comprising administering VX-702 and one or more additional therapeutic agents for RA. In one embodiment, an additional therapeutic agent that can be used with VX-702 is methotrexate. In another embodiment, methotrexate is administered in an amount of about 1 to about 30 mg per week. In yet another embodiment, methotrexate is administered in an amount of about 2.5 to about 30 mg per week. In yet another embodiment, methotrexate is administered in an amount of about 5 to about 20 mg per week. In yet another embodiment, methotrexate is administered in an amount of about 5 to about 10 mg per week. In another embodiment, methotrexate is administered twice a week, once a week, once every two weeks or once a month. In another embodiment, methotrexate is administered once a week. In general, methotrexate can be administered orally, as a pill or liquid formulation, or it can be administer intravenously. One or more therapeutic agents may also be used in addition to VX-702 and methotrexate. In another embodiment, additional therapeutic agents include biological agents. In another embodiment, one or more biological agents are selected from a tumor necrosis factor (TNFa) antagonist, an interleukin-a (IL-a) antagonist, a CD28 antagonist, and a CD20 antagonist. In still another embodiment, one or more biological agents are selected from the group consisting of etanercept (ENBREL ™), adalimumab (HUMIRA ™), infliximab (REMICADE ™), anakinra (KINERET ™), abatacept (ORENCIA ™), rituximab (RITUXAN ™) and certolizumab pegol (CIMZIA ™). One or more other therapeutic agents may also be used in addition to VX-702 and one or more biological agents. As recognized by expert professionals, VX-702 is preferably administered orally. Some of the additional therapeutic agents for RA may be administered orally or may be administered differently, such as intravenously, intramuscularly, parenterally or by local injection at the site of inflammation. However, none of the present limits the methods or combinations of this invention to any of the specific dosage forms or regimen. Accordingly, each component of a combination according to this invention may be administered separately, jointly or in any of its combinations The methods of the present invention may involve the administration or co-administration of a) combinations of f VX-702 and one or more other therapeutic agents for RA; or b) VX-702 in more than one dosage form. Coadministration includes administering each inhibitor in the same dosage form or in different dosage forms. When administered in different dosage forms, the inhibitors may be administered at different times, which include approximately simultaneously or in any period of time around the administration of the other dosage forms. The separate dosage forms can be administered in any order. That is, any of the dosage forms can be administered before, along with, or after the other dosage form. VX-702, and any one or more additional therapeutic agents, can be formulated in separate dosage forms. Alternatively, to reduce the number of dosage forms administered to a patient, VX-702, and any additional agent, can be formulated together in any combination. Any of the separate dosage forms can be administered at the same time or at different times. It should be understood that the dosage forms should be administered within a period of time such that the biological effects are advantageous.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic and the like, and they are proportional with a reasonable risk / benefit ratio. A "pharmaceutically acceptable salt" means a non-toxic salt, which after administration to a recipient, is capable of providing a compound of this invention. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., Describe the pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic or organic acids and bases Examples of pharmaceutically acceptable salts are non-toxic acid addition salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid , phosphoric acid. sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods employed in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodhydrate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, salts of valerate and the like. Salts derived from the appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4 alkyl) 4 salts. This invention also provides for the quaternization of any of the basic nitrogen containing groups and the compounds described herein. Water-soluble or liposoluble or dispersible products can be obtained by quaternization. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using such counterions. as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or carrier, which as used herein, includes any and all solvents, diluents or other liquid carriers, dispersion or suspension aids. , surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. Except to the extent that any conventional carrier medium is incompatible with the compounds of the invention, such as by the production of any undesirable biological effect or otherwise interacting in deleterious manner with any other component (s) of the pharmaceutically acceptable composition. , its use is contemplated within the scope of this invention. Some examples that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, phosphate of disodium hydrogen, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool grease, sugars such as lactose, glucose and saccharose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, in addition to other non-lubricating compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, Coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the criteria of the formulator. The compounds used in the compositions and methods of this invention can also be modified by the appropriate appended functionalities to improve the selective biological properties. Modifications are known in the art and include those that increase biological penetration in a given biological system (eg, blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, They alter the metabolism and alter the rate of excretion. According to a preferred embodiment, the compositions of this invention are formulated for pharmaceutical administration to a mammal, in particular a human. The pharmaceutical compositions of the present invention (in addition to the compositions for use in the methods, combinations, kits and containers of this invention) can be administered orally, parenterally, sublingually, by aerosol inhalation, topically, rectally, nasally. , oral, vaginal or by means of an implanted reservoir. The term "parenteral" as used herein includes injection subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial or infusion techniques. Preferably, the compositions are administered orally or intravenously. More preferably, the compositions are administered orally. The sterile injectable forms of the compositions and according to this invention can be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable for parenteral use, for example as a solution in 1,3-butanediol. Among the vehicles and suitable solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium, for this purpose, any soft fixed oil including synthetic mono- or diglycerides can be employed. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their versions polyoxiet iladas. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms can also be used for the purposes of the formulation. In the compositions of this invention comprising VX-702 and one or more additional therapeutic agents, VX-702 and the additional agent should be present at dose levels between about 10 to 100%, and more preferably between about 10 to 80% of the dose normally administered in a monotherapy regimen. The pharmaceutical compositions of this invention can be administered in any dosage form acceptable for oral use including, but not limited to, capsules, tablets, troches, powders, granules, suspensions or aqueous solutions. In the case of tablets for oral use, vehicles that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also commonly added. For the oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may also be added. Acceptable liquid dosage forms include emulsions, solutions, suspensions, syrups and elixirs. Alternatively, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will consequently melt in the rectum to release the drug. The materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention can also be administered topically. As is recognized in the art, pharmaceutical compositions can also be administered in the form of liposomes. Applicants have shown that VX-702 is bioavailable orally. Accordingly, the preferred pharmaceutical compositions of this invention are formulated for oral administration.

The administration of VX-702 in relation to this invention can be used as chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary according to the host treated and the particular mode of administration. A typical preparation will contain from about 0.5% to about 95% active compound (w / w). Preferably, the preparations contain from about 5% to about 90% active compound. After improvement of the pathological condition of a patient, a maintenance dose of a compound, composition or combination of this invention may be administered, as appropriate. Subsequently, the dose or frequency of administration, or both, may be reduced depending on the symptoms, at a level where the improved condition is maintained, when the symptoms have been alleviated to the desired level the treatment should cease. However, patients may require intermittent treatment on a long-term basis after any recurrence of the symptoms of the disease. It should also be understood that a specific dose and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, combination of drugs and the criterion of the attending physician and the severity of the particular disease treated. The pharmaceutical compositions may also be prescribed to the patient in "patient packs" or "pharmaceutical packs" containing the total treatment in a single container, usually a blister pack. Patient packages have an advantage over traditional prescriptions, where a pharmacist divides the patient's supplies of a pharmaceutical agent from a bulk supply, so that the patient always has access to the package insert contained in the patient's package, which is normally lost in traditional prescriptions. It has been shown that the inclusion of a prospect improves the patient's compliance with the doctor's instructions. It will be understood that the administration of the combination of the invention by means of a single patient package, or patient packs of each formulation, containing within it a package insert which instructs the patient in the correct use of the invention is a desirable additional feature of the invention. this invention. According to another aspect of the invention is a package comprising at least VX-702 (in doses according to this invention) and an information leaflet containing directives for the use of the combination of the invention. Any The composition, dosage form, therapeutic regimen or other embodiment of this invention can be presented in a pharmaceutical container. In an alternative embodiment of this invention, the pharmaceutical pack further comprises one or more additional therapeutic agents as described herein. The additional therapeutic agent or agents may be provided in the same container or in separate containers. In one embodiment, the additional therapeutic agent is methotrexate. Another aspect of this invention involves a packaged kit for a patient for use in the treatment of RA, comprising: a single pharmaceutical formulation or a plurality thereof of VX-702; a container containing the pharmaceutical formulation (s) during storage and before administration; and instructions for carrying out drug administration in an effective manner to treat RA. In another embodiment, the packaged kit further comprises one or more pharmaceutical formulations comprising additional therapeutic agents useful for treating RA. Accordingly, this invention provides kits for the simultaneous or sequential administration of a dose of VX-702 and one or more additional therapeutic agents. Typically, the kit will comprise, for example, a composition of each compound and optional additional agents in a vehicle pharmaceutically acceptable (and in one or a plurality of pharmaceutical formulations) and written instructions for simultaneous or sequential administration. In one embodiment, the additional therapeutic agent is methotrexate. In another embodiment, a packaged kit containing one or more dosage forms for self-administration is provided; a container means, preferably sealed, to house the dosage forms during storage and before use and instructions for a patient to carry out the administration of the drug. The instructions will normally be instructions written on a package insert, label and / or other components of the kit, and the dosage form or forms are as described herein. Each dose form can be housed individually, as in a sheet of plastic sheeting and sheet metal with each dose form isolated from the others in individual cells or bubbles or the dosage forms can be housed in a single container, as in a plastic bottle. The present kit will usually also include packaging means for the individual components of the kit, ie, the dosage forms, the container medium and the written instructions for use. The packaging means can take the form of a cardboard or paper box, a plastic or metal bag, etc. A kit according to this invention could represent any aspect of this invention such as any composition, dosage form, therapeutic regimen or pharmaceutical container. The packages and kits according to this invention optionally comprise a plurality of compositions or dosage forms. Accordingly, packages and kit containing a composition or more than one composition should be included within this invention. While certain examples of embodiments are depicted and described below, it will be appreciated that the compounds of this invention can be prepared according to the methods generally described above using appropriate starting materials generally available to those skilled in the art. art. In order for this invention to be fully understood, the following example is set forth. This example is for illustrative purposes only and is not to be construed as limiting the scope of the invention in any way. EXAMPLE 1 VX-702 was examined in a graded, blind, multiple dose, randomized, placebo-controlled dose study in 315 subjects with moderate or severe RA. The subjects were divided into 3 groups of approximately equal size of 100-105 subjects each. In one group, subjects received 5 mg of VX-702 once per day or 2.5 mg of VX-702 twice per day (total 5 mg / day) for twelve weeks Another group received 10 mg of VX-702 once a day for twelve weeks. Another group of subjects received placebo once a day for twelve weeks. The compositions used in this study were the following: The subjects must be between 18-75 years old (inclusive) and have an active RA of six months or longer according to the revised ACR criteria. The subjects had to have serum levels of C-reactive protein (CRP) of more than 2 mg / dL at the time of randomization, a number of swollen joints of eight or more (out of 28) and the number of joints sensitive to palpation of 10 or more (out of 28). Subjects should not be previously treated with disease-modifying antirheumatic drug therapy (DMARD) or inadequately re-exposed to therapy with DMARD. If a subject had received prior treatment with an antibody or TNF-binding protein (anti-TNF) or with the recombinant IL-1 receptor antagonist (IL-IRa), the subject may have discontinued the treatment due to tolerance reasons but not having discontinued the treatment due to due to an inadequate response. Subjects must also have discontinued CMARD therapy (except for sulfasalazine or hydroxychloroquine) for at least one month prior to randomization. Subjects could receive an NSAID and / or prednisone (< 10 mg / day) if they had been treated with a stable dose for at least one month prior to randomization. Safety assessments were also conducted in the study.

These included physical exams, which included measurements of vital signs (which included blood pressure, heart rate, respiratory rate and temperature); clinical laboratory evaluations (hematology, chemistry and urinalysis); Creatinine clearance; adverse events; Holter monitoring and electrocardiogram (ECG) (12 leads). Treatment responses were evaluated for changes in the ACR (for example, ACR2o) or EULAR criteria. The responses to the treatment were measured in weeks 2, 4, 6, 8, 10 and 12. The safety assessments were also made in these points of weather. Holter monitoring and electrocardiogram were not performed at all time points. Four weeks after the end of the study, the evaluations of response to treatment and safety in the subjects were carried out. Preliminary definition of improvement ACR in the RA (ACR2p): Required: > 20% improvement in the number of joints sensitive to palpation > 20% improvement in the number of inflamed joints AND at least 20% improvement in 3 of the following 5: Assessment of the subject's pain Overall evaluation of the subject Overall evaluation of the physician Self-assessed disability by the subject Acute phase reactant (CRP or ESR) Measurement of the activity of the disease evaluation method Number of joints Number of joints sensitive to palpation sensitive to palpation ACR, an evaluation of 28 joints. The counting of the joints should be done by classifying several different aspects of palpation sensitivity, evaluated pressure and manipulation of the joints in the physical examination. Information of various types of palpation sensitivity should then be folded to the sensitive single dichotomy versus not sensitive to palpation. Number of joints Number of swollen inflamed joints of ACR, an evaluation of 28 joints. The joints are classified as inflamed or non-inflamed. Pain assessment A horizontal pain VAS (0-100 mm) is used to assess the patient's current pain level Overall assessment of the subject The overall assessment of the subject of his arthritis is document with a scale of 1-10 Overall assessment of the physician The overall assessment of the physician's activity of the subject's disease is documented on a scale of 1-10 Self-assessed impairment The HAQ self-assessment instrument that measures physical function in subjects with RA is acceptable, validated, conflatable, and shown in RA trials to be sensitive to changes. Acute phase reactant Westergreen erythrocyte sedimentation rate or level of C-reactive protein The responses of ACR50 and ACR70 require improvement responses > 50% and > 70%, respectively with the same criteria described for the response of ACR20- Response criterion of EULAR EULAR is described in Fransen et al., Clinical and Experimental Rheumatology 23 (Suppl 39): S93-99, 2005, which is hereby incorporated by reference in its entirety. EULAR is based on disease activity score (DAS), a clinical index of RA disease activity that combines information from inflamed joints, palpation-sensitive joints, acute phase responses, and general health in a continuous measure of rheumatoid inflammation. The DAS28 is an index similar to the DAS original, which consists of the count of 28 joints sensitive to palpation (range 0-28), a count of 28 inflamed joints (range 0-28), erythrocyte sedimentation rate (ESR) and an optional general health assessment in a visual analog scale (range 0-100).

Safety results VX-702 was well tolerated with a treatment discontinuation rate due to low adverse events similar to that observed in the placebo group. Premature discontinuations due to adverse events occurred in 2% of patients receiving placebo, 3% of patients with 5 mg of VX-702 and 5% of patients with 10 mg of VX-702. The most common adverse events that led to the discontinuation of treatment were observed in two patients and were the following: gastroenteritis, nausea / vomiting, rash and renal deterioration (increased serum creatinine). No patient discontinued treatment for elevations of hepatic function tests. Adverse events were reported in 2% of patients treated with placebo, and 4-7% of patients treated with VX-702. Gastroenteritis was the only serious adverse event reported in more than one patient. The most common adverse events were generally classified as mild or moderate and were infections (upper respiratory infections, gastroenteritis, nasopharyngitis, etc.), observed in 10% of patients treated with VX-702 versus 5% of placebo recipients; gastrointestinal disorders (nausea, vomiting, diarrhea) observed in 8% of patients treated with VX-702 versus 6% of placebo recipients; and skin disorders (rash, acne, itching) observed in approximately 9% of patients treated with VX-702. Clinically significant effects on clinical parameters, including liver function tests, were not evident. At each treatment visit, 2-4% of patients treated with VX-702 and 1-2% of placebo recipients exhibited a high ALT value that was above the upper normal limit. No patient developed an ALT elevation of three times the normal upper limit, which would have required discontinuation. The extended Holter (24 to 72 hours of continuous electrocardiogram (EG) monitoring performed 6 times / patient during the study) revealed no difference in ectopic ventricular activity rates between patients receiving placebo and those receiving VX-702, and did not reveal an increased tendency to arrhythmias with treatment with VX-702. Digital electrocardiograms revealed a minimal increase in the QT interval: from a baseline QTcF (corrected Fridericia QT) of approximately 400 msec to the end of treatment, patients on placebo demonstrated a change mean of -0.6 msec, while patients of VX-702 exhibited an average increase of 3 and 6 msec of QTcF in the groups of 5 and 10 mg, respectively. No patient showed a maximum QTcF increase of > 60 msec at any point in the study.

Effects on the signs and symptoms of rheumatoid arthritis The results of the final analysis of the study showed that there was a statistically significant dose-dependent increase in the response rates of ACR20 with the treatment of VX-702: 28% of the placebo recipients 36% of patients treated with VX-702 5 mg and 40% of patients treated with VX-702 obtained an ACR20 response (p = 0.02, Jonckheere-Terpstra test for increasing dose response). In addition, 32% of the placebo recipients, 40% of the patients treated with 5 mg with 702 and 44% of the patients treated with 10 mg of VX-702 obtained an EULAR response (moderate or good) (p = 0.02 ). Statistically significant dose-dependent effects were also shown for the percent improvement in DAS28. ACR20, EULAR, DAS28, percent of change of the joints sensitive to palpation changes of percent in inflamed joints and reduction of morning stiffness are presented in the following table: End of treatment (Week 12) Placebo 5 mg of 10 mg p-value VX-702 VX-702 Response ACR 20 28% 36% 40% 0, 02 Response EULAR 32% 40% 44% 0, 02 Basal improvement in DAS28 -0.8 -1.0 -1.2 0, 012 Percent of -12% -15% -18% 0, 009 improvement in DAS Percent change in -22% -28% -36% ND joints sensitive to palpation Percent change in -28% -35% - 46% ND inflamed joints Average reduction in stiffness -3, 0 -98 -82 < 0, 001 morning (minutes) Percent of 7.2% -21.6% -2.7% < 0, 001 reduction in morning stiffness All the mentioned documents are incorporated herein by reference. While several embodiments of this invention have been described, it is evident that our basic examples are they may alter to provide other embodiments utilizing the compounds and methods of this invention. Accordingly, it will be appreciated that the scope of this invention is defined by the appended claims rather than by the specific embodiments that have been exemplified above. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (66)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical composition characterized in that it comprises VX-702, or a pharmaceutically acceptable salt thereof, in an amount effective to treat rheumatoid arthritis, and a vehicle pharmaceutically acceptable.
2. 2. A pharmaceutical composition characterized in that it comprises VX-702, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 20 mg of VX-702, and a pharmaceutically acceptable carrier.
3. 3. The pharmaceutical composition according to claim 2, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.5 mg to about 15 mg of VX-702.
4. 4. The pharmaceutical composition according to claim 3, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of about 2.5 mg to about 12.5 mg of VX-702.
5. 5. The pharmaceutical composition according to claim 4, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount from about 4 mg to about 11 mg of VX-702.
6. 6. The pharmaceutical composition according to claim 5, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of 4 mg, 5, mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg or 11 mg of VX-702.
7. 7. The pharmaceutical composition according to claim 5, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg to about 10 mg of VX-702.
8. 8. The pharmaceutical composition according to claim 7, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of 5 mg or 10 mg of VX-702.
9. 9. A pharmaceutical composition characterized in that it comprises VX-702, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 40 mg of VX-702, and a pharmaceutically acceptable carrier.
10. 10. The pharmaceutical composition according to claim 9, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is present in an amount of about 30 mg to about 40 mg of VX-702.
11. 11. The pharmaceutical composition according to claim 9, characterized in that VX-702, or one of its pharmaceutically acceptable salts, an amount of about 20 mg to about 30 mg of VX-702 is present.
12. 12. A method of treating rheumatoid arthritis in a subject in need thereof, characterized in that it comprises administering VX-702, or a pharmaceutically acceptable salt thereof, in an amount effective to treat rheumatoid arthritis in the patient.
13. 13. The method according to claim 12, characterized in that the amount is that which is effective to alleviate the severity of the symptoms of rheumatoid arthritis as measured by ACR2o- 14.
14. A method of treating rheumatoid arthritis in a subject in need, characterized because it comprises administering the subject VX-702, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 20 mg per day.
15. The method according to claim 14, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 2.5 mg to about 15 mg of VX-702.
16. The method according to claim 15, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 2.5 mg to about 12.5 mg of VX-702.
17. 17. The method according to claim 16, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 4 mg to about 11 mg of VX-702.
18. The method according to claim 17, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is 4 mg, 5, mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg u 11 mg of VX-702.
19. 19. The method according to claim 17, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 5 mg to about 10 mg of VX-702.
20. The method according to claim 19, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is 5 mg or 10 mg of VX-702.
21. 21. A method of treating rheumatoid arthritis in a subject in need thereof, characterized in that it comprises administering the subject VX-702, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg to about 40 mg per day.
22. 22. The method according to claim 21, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 30 mg to about 40 mg of VX-702.
23. 23. The method according to claim 21, characterized in that the amount of VX-702, or one of its salts pharmaceutically acceptable, is about 20 mg to about 30 mg of VX-702.
24. 24. The method according to any of claims 12-20, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered one, two, three times per day.
25. 25. The method according to claim 24, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once or twice per day.
26. 26. The method according to claim 25, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once per day.
27. 27. The method according to any of claims 21-23, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once, two or three times per day.
28. The method according to claim 27, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once or twice per day.
29. 29. The method according to claim 28, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once per day.
30. 30. The method of compliance with any of the claims 12 or 13, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered once a week, twice a week, every three days or every other day.
31. 31. The method according to claim 30, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 2.5 mg to about 40 mg per day.
32. 32. The method according to claim 31, characterized in that the amount of VX-702, or one of its pharmaceutically acceptable salts, is about 2.5 mg to about 20 mg per day.
33. The method according to any of claims 12-20 or 24-26, characterized in that VX-702, or one of its pharmaceutically acceptable salts, is administered as a pharmaceutical composition.
34. 34. The method according to any of claims 21-23 or 27-32, characterized in that VX-702, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition.
35. 35. A method of treating rheumatoid arthritis in a subject in need thereof, characterized in that it comprises administering the subject VX-702 in an amount of 5 mg to 10 mg per day.
36. 36. The method according to claim 35, characterized in that the VX-702 is administered once a day or twice daily.
37. 37. The method according to claim 36, characterized in that the VX-702 is administered once per day.
38. 38. The method according to any of claims 12-20, 24-26, 33 or 35-37, characterized in that it comprises administering one or more additional therapeutic agents for rheumatoid arthritis.
39. 39. The method according to claim 38, characterized in that the one or more additional therapeutic agents are selected from the group consisting of a non-spheroid anti-inflammatory drug, an anti-inflammatory spheroid, methotrexate, a gold compound, an antimalarial, cyclosporine, leflunomide , azathioprine, sulfasalazine, d-penicillamine, cyclophosphamide and mycophenolate.
40. 40. The method according to claim 39, characterized in that the one or more additional therapeutic agents is methotrexate.
41. 41. The method according to claim 40, characterized in that the methotrexate is administered in an amount of about 2.5 to about 30 mg per week.
42. 42. The method according to claim 41, characterized in that the methotrexate is administered in an amount of about 5 to about 10 mg per week.
43. 43. The method according to any of claims 40-42, characterized in that methotrexate is administered once a week.
44. 44. The method according to any of claims 21-23, 27-32 or 34, characterized in that it comprises administering one or more additional therapeutic agents for rheumatoid arthritis.
45. 45. The method according to claim 44, characterized in that the one or more additional therapeutic agents are selected from the group consisting of a non-steroidal anti-inflammatory drug, an anti-inflammatory spheroid, methotrexate, a gold compound, an antimalarial, cyclosporine, leflunomide , azathioprine, sulfasalazine, d-penicillamine, cyclophosphamide and mycophenolate.
46. 46. The method according to claim 44, characterized in that the one or more additional therapeutic agents is methotrexate.
47. 47. The method according to claim 46, characterized in that methotrexate is administered in an amount of about 2.5 to about 30 mg per week.
48. 48. The method according to claim 47, characterized in that methotrexate is administered in an amount of about 5 to about 10 mg per week.
49. 49. The method according to any of claims 46-48, characterized in that methotrexate is administered once a week.
50. 50. The method according to any of claims 38 or 44, characterized in that the one or more additional therapeutic agents are selected from one or more biological agents.
51. 51. The method according to claim 50, characterized in that the one or more biological agents are selected from the group consisting of a tumor necrosis factor a (TNFa) antagonist, an interleukin-1 a (IL-? A) antagonist. ), a CD28 antagonist and a CD20 antagonist.
52. 52. The method according to claim 51, characterized in that the one or more biological agents are selected from the group consisting of etanercept (ENBREL ™), adalimumab (HUMIRA ™), infliximab (REMICADE ™), anakinra (KINERET ™), abatacept (ORENCIA ™), rituximab (RITUXAN ™) and certolizumab pegol (CIMZIA ™).
53. 53. A pharmaceutical package characterized in that it comprises a composition comprising VX-702 or a pharmaceutically acceptable salt thereof according to any of claims 1-8, or a composition or dosage form comprising VX-702 or one of its salts pharmaceutically acceptable to practice the method of according to any of claims 12-20, 24-26, 33 or 35-39.
54. 54. The pharmaceutical pack according to claim 53, characterized in that the pharmaceutical pack comprising a composition or dosage form comprising VX-702 or a pharmaceutically acceptable salt thereof, and methotrexate or one of its pharmaceutical compositions.
55. 55. A pharmaceutical package characterized in that it comprises a composition comprising VX-702 or a pharmaceutically acceptable salt thereof according to any of claims 9-11, or a composition or dosage form comprising VX-702 or a salt thereof. pharmaceutically acceptable to practice the method according to any of claims 21-23, 27-32, 34 or 40-52.
56. 56. The pharmaceutical pack according to claim 55, characterized in that the pharmaceutical pack comprising a composition or dosage form comprising VX-702 or a pharmaceutically acceptable salt thereof, and methotrexate or one of its pharmaceutical compositions.
57. 57. A kit characterized in that it comprises a composition comprising VX-702 or a pharmaceutically acceptable salt thereof according to any of claims 1-8, or a composition or dosage form comprising VX-702 or a pharmaceutically acceptable salt thereof. acceptable to practice the method according to any of claims 12-20, 24-26, 33 or 35-39.
58. 58. The kit according to claim 57, characterized in that it comprises a composition or dosage form comprising VX-702 or one of its pharmaceutically acceptable salts, and methotrexate or one of its pharmaceutical compositions.
59. 59. A kit characterized in that it comprises a composition comprising VX-702 or a pharmaceutically acceptable salt thereof according to any of claims 9-11, or a composition or dosage form comprising VX-702 or a pharmaceutically acceptable salt thereof. acceptable to practice the method according to any of claims 21-23, 27-32, 34 or 40-52.
60. 60. The kit according to claim 59, characterized in that the kit comprises a composition or dosage form comprising VX-702 or a pharmaceutically acceptable salt thereof, and methotrexate or one of its pharmaceutical compositions.
61. 61. The package according to claim 53 or the kit according to claim 57, characterized in that it comprises a plurality of compositions or dosage forms comprising VX-702 or a pharmaceutically acceptable salt thereof.
62. 62. The package according to claim 54 or the kit according to claim 58, characterized in that it comprises a plurality of compositions or dosage forms comprising VX-702 or a pharmaceutically acceptable salt thereof, and a plurality of compositions or dosage forms comprising methotrexate or one of its pharmaceutical compositions.
63. 63. The package according to claim 55 or the kit according to claim 59, characterized in that it comprises a plurality of compositions or dosage forms comprising VX-702 or one of its pharmaceutically acceptable salts.
64. 64. The package according to claim 56 or the kit according to claim 60, characterized in that it comprises a plurality of compositions or dosage forms comprising VX-702 a plurality of compositions or dosage forms comprising VX-702 or one of its pharmaceutically acceptable salts, and a plurality of compositions or dosage forms comprising methotrexate or one of its pharmaceutical compositions.
65. 65. A pharmaceutical composition characterized in that it comprises VX-702 or a pharmaceutically acceptable salt thereof.
66. 66. The composition according to claim 65, characterized in that the composition comprises about 1 to about 40 mg of VX-702, about 10 to about 20% of dibasic calcium phosphate, about 10 to about 20% of microcrystalline cellulose, about 0.1 to about 1.0% of sodium lauryl sulfate, about 0.1 to about 2.5% of croscarmellose sodium, about 0.0 to about 1% of colloidal silicon dioxide, about 0.1 to about 5% of magnesium stearate and about 10 to about 70% of lactose monohydrate.